Department of Molecular Immunology and Toxicology, National Institute of Oncology, Ráth György utca 7-9, Budapest 1122, Hungary.
Department of Chemistry, University of Puerto Rico, Mayagüez Campus, P.O. Box 9019, Mayagüez, PR 00681-9019, United States.
Free Radic Biol Med. 2017 Dec;113:551-563. doi: 10.1016/j.freeradbiomed.2017.10.384. Epub 2017 Oct 31.
The interaction of heme proteins with hydrogen sulfide is gaining attention as an important element in sulfide-mediated protection against oxidative stress and in regulation of redox signaling. In our previous study we reported the efficient reversible inhibition of myeloperoxidase (MPO) activity by sulfide and the kinetics of the reactions of sulfide with ferric MPO, Compound I and Compound II. Here we provide several lines of evidence that a central intermediate species in the turnover of MPO by sulfide is the Compound III state. Compound III is formed in the reactions of sulfide with ferric or ferrous MPO in the presence of oxygen or via the reductions of Compound I or Compound II by sulfide. The regeneration of active ferric MPO from Compound III is slow - representing the rate-limiting step during turnover - but facilitated by ascorbate or superoxide dismutase. These catalytic cycles produce inorganic sulfane sulfur species, which were shown to promote protein Cys persulfidation. Based on compiling experimental data we propose that in contrast to hemoglobin, myoglobin, catalase or lactoperoxidase the formation of a sulfheme derivative in the oxidative interactions of sulfide with MPO is not a major pathway. Using the Met243Val mutant we demonstrated that the sulfonium ion linkage of the Met243 sulfur to the heme pyrrole ring A, which is a unique feature of MPO, is pivotal in the catalytic oxidation of sulfide via Compound III. The proposed novel MPO-catalyzed sulfide oxidation model does not require the initial presence of hydrogen peroxide, only oxygen to provide a slow flux of sulfane sulfur species generation, which could be important in sulfide-mediated endogenous signaling. Furthermore, peroxide-induced formation of sulfane sulfur species by MPO may have a role in protection of regulatory or functional Cys residues during (for example neutrophil induced) inflammatory oxidative stress.
血红素蛋白与硫化氢的相互作用作为硫介导的抗氧化应激保护和调节氧化还原信号中的一个重要因素受到关注。在我们之前的研究中，我们报道了硫化氢对髓过氧化物酶（MPO）活性的有效可逆抑制作用，以及硫化氢与三价 MPO、复合物 I 和复合物 II 的反应动力学。在这里，我们提供了几条证据表明，硫化氢在 MPO 循环中一种中心中间物种是复合物 III 状态。在氧存在下或通过硫化氢还原复合物 I 或复合物 II，复合物 III 在硫化物与三价或二价 MPO 的反应中形成。从复合物 III 中再生活性三价 MPO 是缓慢的 - 代表循环中的限速步骤 - 但被抗坏血酸或超氧化物歧化酶促进。这些催化循环产生无机硫烷硫物种，其被证明可促进蛋白半胱氨酸过硫化。基于编译的实验数据，我们提出与血红蛋白、肌红蛋白、过氧化氢酶或乳过氧化物酶不同，在硫化物与 MPO 的氧化相互作用中形成硫血红素衍生物不是主要途径。使用 Met243Val 突变体，我们证明了 MPO 中独特的 Met243 硫与血红素吡咯环 A 的亚砜离子键在通过复合物 III 催化硫化物氧化中至关重要。所提出的新型 MPO 催化的硫化物氧化模型不需要初始存在过氧化氢，只需要氧来提供缓慢的硫烷硫物种生成通量，这在硫介导的内源性信号中可能很重要。此外，MPO 诱导的过氧化物形成的硫烷硫物种可能在（例如，中性粒细胞诱导的）炎症性氧化应激期间对调节或功能半胱氨酸残基的保护中发挥作用。
